Several studies were designed to investigate strategies to improve endothelial dysfunction in patients with atherosclerosis and its risk factors. Angiotensin converting enzyme (ACE) inhibition with enalaprilat acutely improved endothelium-dependent vasodilation in the coronary and peripheral vasculature of patients with atherosclerosis and its risk factors. This improvement was due to increased nitric oxide (NO) bioavailability with ACE inhibitors. Current studies are examining whether A)angiotensin II receptor blockade improves endothelial function, B)ACE genotype influences endothelial function, C) whether the improvement in function with ACE inhibitors is dependent on the ACE gene polymorphism, D) whether ACE inhibitors improve myocardial ischemia. A) ACE inhibition in coronary disease(CAD)improves endothelial dysfunction which may be secondary to enhancement of bradykinin or inhibition of angiotensin (AT)II. We therefore examined the acute and chronic effects of AT type I (AT1) receptor blockade with losartan on vascular endothelial function. Acute study: In 19 patients with CAD or its risks, femoral Doppler flow velocity (FV) was measured during intraarterial (ia)infusions of acetylcholine (ACH, 150,300 mcg/min), nitroprusside (NTP)(40 mcg/min) and AT II (100,1000 pmol/min), before and after 10mg ia losartan. Acute ia losartan inhibited constriction with AT II (33 to 20% reduction in FV, P<0.001) and enhanced femoral microvascular dilation in response to ACH (39% increase in FV, and 7% increase in femoral venous oxygen saturation at 150mcg/min ACH, both P<0.001). The response to NTP was unaltered. Chronic study: In 31 patients with CAD, brachial artery diameter was measured using ultrasound during flow-mediated dilation (FMD)in response to hyperemia, and after nitroglycerin, before and after 2 months of oral losartan (25 to 50 mg, median 50 mg). FMD of the brachial artery increased from 1.4 +/-.9% before to 3.2+/-.8%, P=0.03 after losartan,whereas dilation in response to nitroglycerin 8+/-.8% vs. 8.8+/-1%,P=0.7 was similar. Conclusions:AT1 receptor inhibition with losartan selectively improved peripheral microvascular endothelial dysfunction acutely, and brachial FMD after long term oral therapy. Thus, AT II receptor-activated increase in oxygen free radicals may contribute to endothelial dysfunction in CAD, and AT1 receptor inhibiton, by improving NO bioavailability, may contribute to longterm improvement of vascular function and reduction in adverse events. B) The presence of the deletion (D) allele in the ACE gene is a risk factor in the pathogenesis of CAD. We hypothesized that this deleterious effect of the polymorphism is due to an adverse effect on coronary vasomotor function. In 133 pts with CAD or its risk factors, endothelium-dependent and -independent vasodilaton was assessed with i.c. infusions of ACH and NTP respectively. In 76 pts, we estimated basal NO production by inhibiting NO synthase by i.c. L-NMMA. Coronary epicardial diameter (ED) and blood flow velocity were measured by quantitative angiography and Doppler wire respectively. ACE genotypes were determined by PCR. Dilation in response to ACH did not differ between genotypes, but the response to NTP was depressed in those with the D allele. L-NMMA induced greater vasoconstriction in pts with the DD genotype. Our results indicate that the D allele of the ACE gene (i) does not contribute to the ACH response, (ii) is associated with increased basal constrictor tone which may predispose to the observed increased risk of myocardial infarction and (iii) is associated with enhanced basal NO production which may be a compensatory mechanism to the increased constrictor tone. C) Atherosclerosis is associated by upregulated vascular ACE activity and endothelial dysfunction. We therefore also investigated whether 1)ACE inhibition with enalaprilat (EN) improves coronary vascular endothelial dysfunction and 2)this correlates with the presence of the D allele. EN selectively improved ACH-mediated microvascular dilation (42% to 49% reduction in vascular resistance, p=0.002 and epicardial constriction 9% to 2.5% reduction in diameter, P<0.001). However, this improvement was significant only in patients with the D genotype; the 10% further reduction in vascular resistance with EN in those with the D allele was greater than the 7% increase in patients with II genotype, p=0.04. Similarly, improvement by EN in ACH-mediated epicardial narrowing was significant only in patients with the D allele (9.4% to 2.1%, P<0.001), and not in those with II genotype (8.5% to 3.5%, p=0.1). The presence of the D allele and baseline endothelial function were the independent determinants of improvement in function with EN.